Filaggrin, the processed form of profilaggrin, is a major product of terminally differentiating mammalian epidermis. Based on in vitro experiments, fillaggrin is thought to be involved in the aggregation and specific alignment of keratin intermediate filaments during the final stages of development in the epidermis in vivo. This hypothesis has been explored by stable transfection into keratinocytes of a vector containing one fillaggrin repeat under the control of an inducible promoter. Upon activation of the promoter, the expressed filaggrin disrupts the keratin cytoskeleton due to aggregation of the filament near the nucleus, causes major shape changes in the cells. The cells die within 6 hours by apoptosis. We have explored the regulation of expression of the profilaggrin gene and have characterized the proximal promoter. An AP1 site and its cognate binding c-fos and c-jun proteins confer keratinocyte-specific expression to the gene, in concert with neighboring Sp1, ets-like, and NF-KB elements. We have discovered a novel ets transcription protein that seems to function in the regulation of expression of several genes in the epidermis, including profilaggrin.